Carboxylated polyphenol derivatives and their cosmetic use

ABSTRACT

A subject matter of the present invention is the cosmetic use of at least one compound of formula (I): in which: (II) denotes a divalent radical chosen from a carbon-carbon single bond *—CH 2 —CH 2 —* or double bond *—CH═CH—*, of Z or E configuration or their mixtures, b=0 or 1, c=0 or 1, d=0, 1 or 2, and R and R′ independently denote a hydrogen atom, a linear C 1 -C 6  alkyl radical or a branched C 3 -C 6  alkyl radical, to treat and/or prevent signs of aging and/or of photoaging of keratinous substances, preferably of the skin, and/or to depigment, lighten and/or whiten keratinous substances, preferably the skin. The present invention also relates to novel compounds and to a corresponding cosmetic method.

The present invention relates to the field of the treatment of the signsof aging of keratinous substances, in particular human keratinoussubstances, and more particularly of the skin, and also to the field ofthe depigmentation and/or lightening and/or whitening of the skin.

More particularly, the invention relates to the cosmetic use of at leastone compound of formula (I) as defined below, namely a carboxylatedpolyphenol derivative, for the purpose of decreasing and/or delaying thesigns of aging of keratinous substances and in particular of the skinand/or also for the purpose of depigmenting and/or lightening and/orwhitening the skin. The invention also relates to novel compounds offormulae (III) to (V) as defined below.

Human skin is made up of three compartments, namely a superficialcompartment, which is the epidermis, the dermis, and a deep compartment,which is the hypodermis.

The dermis provides the epidermis with a solid support. It is also itsnourishing element. It is mainly constituted of fibroblasts and anextracellular matrix (ECM).

This extracellular matrix is constituted of various macromoleculesresponsible for the mechanical strength of the skin, for its suppleness,for its tonicity and for its elasticity, and also for the importantphysiological functions (moisturization, thermoregulation and regulationof skin permeability). Among these macromolecules are in particularcollagens, glycosaminoglycanes (GAG), elastin and glycoconjugates(glycoproteins and proteoglycans).

Collagens represent 70% of the ECM proteins. In the skin, numerous typesof collagen constitute the ECM, including in particular the interstitialcollagens (type I, II, III collagens) of fibrillar structure, producedessentially by the fibroblasts, and responsible for the cohesion, therigidity and the mechanical strength, the collagens of the basal lamina(type IV collagens) synthesized by the adjacent cells and in the skin bythe keratinocytes and which play in particular a mechanical role, andthe collagens which form fibrils for anchoring of the basal membrane(dermis-epidermis link) expressed by the epidermal keratinocytes (typeVII collagens).

It is also known that collagen synthesis begins with the assembly ofprocollagen units. For example, for the synthesis of collagen type I,these are units of procollagen type I (also called Pro-Coll1).

Naturally, collagen fibers are constantly renewed, but this renewaldecreases with age, which leads to thinning of the dermis.

The glycosaminoglycans or glycosaminoglycans (GAGs) are optionallysulphated linear chains composed of the repetition of a base diholosidealways containing a hexosamine (glucosamine or galactosamine) andanother ose (glucuronic acid, iduronic acid or galactose). Theglucosamine is either N-sulfated or N-acetylated. In contrast,galactosamine is always N-acetylated. In addition, there may be O-bondedsulfates on hexosamine, uronic acid and galactose.

The strong anionic nature of GAGs is explained by the presence ofcarboxylate groups in hexuronic acids (glucuronic acid and iduronicacid) and O- and N-linked sulfate groups.

GAGs are forming an important component of connective tissue. The GAGchains may be covalently linked to a protein to form proteoglycans.

GAGs are naturally present in the skin, in the extracellular matrix ofthe dermis.

GAGs have long been referred to as acid mucopolysaccharides due to theirhigh water retention capacity, their carbohydrate nature and theiracidic character from their multiple negative charges.

One of the major GAG is hyaluronic acid or hyaluronan (HA).

Hyaluronic acid or hyaluronan (HA) is the main GAG of the dermis, thelatter containing half of HA of the organism. It is a polymer ofdisaccharides themselves composed of D-glucuronic acid andD-N-acetylglucosamine, linked together by alternating beta-1,4 andbeta-1,3 glycosidic bonds. It has a very high intrinsic viscosity,ensuring the assembly of the various elements of the connective tissueby formation of supramolecular complexes. Hyaluronic acid is known asbeing an important constituent of extracellular matrix, playing majorrole for instance in mechanical properties of dermis.

In addition, glycation is a non-enzymatic process involving a saccharide(glucose or ribose) which reacts via the Maillard reaction with an aminegroup of an amino acid residue (for instance lysine), particularly anamino acid residue of a protein, to form a Schiff's base. This base,after an “Amadori” molecular rearrangement, may lead, via a successionof reactions, to bridging, particularly intermolecular bridging, forinstance of pentosidine type.

This phenomenon is characterized by the appearance of glycationproducts, the content of which increases uniformly as a function of age.Glycation products are, for example, pyrraline, carboxymethyllysine,pentosidine, crossline, N^(e)(2-carboxyethyl)lysine (CEL),glyoxal-lysine dimer (GOLD), methylglyoxal-lysine dimer (MOLD), 3DG-ARGimidazolone, versperlysines A, B, C, threosidine, or advancedglycosylation end products (or AGEs).

The glycation of proteins is therefore a universal phenomenon, wellknown in the skin, particularly at the level of the collagen fibers. Theglycation of collagen in fact increases uniformly with age, leading to auniform increase in the content of glycation products in the skin.

Without wishing to introduce any one theory of aging of the skin, itshould be noted that it has been possible to demonstrate during skinaging other changes in collagen which might also be a consequence ofglycation, such as a decrease in heat denaturation, an increase inresistance to enzymatic digestion and an increase in intermolecularbridging (Tanaka S. et al., 1988, J. Mol. Biol., 203, 495-505; TakahashiM. et al., 1995, Analytical Biochemistry, 232, 158-162). Furthermore,glycation-mediated changes in certain constituents of the basal membranesuch as collagen IV, laminin and fibronectin were able to bedemonstrated (Tarsio J F. et al., 1985, Diabetes, 34, 477-484; Tarsio JF. et al., 1988, Diabetes, 37, 532-539; Sternberg M. et al., 1995, C. R.Soc. Biol., 189, 967-985).

It is thus understood that, in the course of aging of the skin, thephysicochemical properties of collagen become modified and collagenbecomes more difficult to dissolve and more difficult to degrade. Astiffening of the tissues follows, resulting essentially in a loss ofskin tonicity.

Moreover, the skin changes due to intrinsic aging are the consequence ofgenetically programmed senescence in which endogenous factors areinvolved. This intrinsic aging causes in particular a slowing of skincell renewal, which is essentially reflected by the occurrence ofdetrimental clinical modifications, such as a reduction in subcutaneousadipose tissue and the appearance of fine wrinkles or fine lines, and byhistopathological changes, such as an increase in the number andthickness of elastic fibers, a loss of vertical fibers of the elastictissue membrane, and the presence of large irregular fibroblasts in thecells of this elastic tissue. The epidermis, which constitutes the upperlayer of the skin, is undergoing constant regeneration. The epidermis isconstituted of several layers of cells, the deepest of which is thebasal layer constituted of undifferentiated cells. Over time, thesecells will differentiate and migrate to the surface of the epidermiswhile constituting the various layers thereof, until they form, at thesurface of the epidermis, the corneocytes which are dead cells that areeliminated by the natural phenomenon of desquamation. This loss at thesurface is compensated for by the migration of cells from the basallayer toward the surface of the epidermis. There is perpetual renewal ofthe skin. The epidermis is therefore constantly engaged in producing newkeratinocytes to compensate for the continuous loss of epidermal cellsat the horny layer. However, in the course of aging, a decrease in thenumber of cells in the proliferation phase, and consequently a decreaseof the live epidermal layers, may be observed physiologically.

The homeostasis of the skin, and in particular of the epidermis, resultsfrom a finely regulated balance between the processes of proliferationand of differentiation of the skin cells. These processes ofproliferation and differentiation are entirely regulated: theyparticipate in the renewal and/or regeneration of the skin and lead tothe maintenance of a constant thickness of the skin, and in particularof a constant thickness of the epidermis. This homeostasis of the skinalso participates in maintaining the mechanical properties of the skin.

However, this homeostasis of the skin may be detrimentally affected bycertain physiological factors (age, menopause, hormones, and the like)or environmental factors (UV stress, oxidative stress, irritant stress,and the like).

The proliferative cells are metabolically very active and are sensitiveto these deleterious factors (intrinsic or environmental), with, as aconsequence on the epidermis, a reduction in their amount. It is thusimportant to preserve these cells in order to contribute towardsdelaying the onset of the signs of aging.

The cell vitality of keratinocytes may be reduced in particular in thecontext of aging or because of oxidative stress (for example solar, i.e.UV, radiation, radiation in the visible range, infrared radiation),because of the epidermis being attacked by toxins or metabolites of themicroflora, or, more generally, during chronological aging. The capacityfor renewal and differentiation of the keratinocytes is reduced and thehomeostasis of structures dependent thereon, such as the barrierfunction of the epidermis, is detrimentally affected.

When the regenerative potential of the epidermis becomes smaller: thecells of the basal layer divide less actively, leading in particular toa slowing-down and/or decrease in epidermal renewal. Consequently, thecell renewal no longer compensates for the loss of cells removed at thesurface, leading to atrophy of the epidermis and/or a reduction in skinthickness.

Detrimental changes in epidermal homeostasis are also reflected by adull and/or off-color appearance of the skin complexion.

Detrimental change of the barrier function is manifested by varioussigns depending on the localization: hyperkeratosis, thin epidermis,surface wrinkles.

The signs associated with a detrimental change of the cellular vitalityof the epidermis thus concern not only its structure, but also itshomeostasis. The resistance to stress of the epidermis and its capacityfor regeneration are reduced. If the skin barrier of an elderly personis compared with that of a young adult, the differences do not appear atfirst sight: the thickness of the horny layer and the composition of itslipids are not necessarily detrimentally changed, and the barrierfunction is preserved. The deficiencies of the elderly skin barrierappear under mechanical stress or during exposure to irritant factors:the barrier of an elderly epidermis degrades more rapidly and itsfunction recovers less quickly. On a daily basis, actions such asalcoholic disinfection or contact with lemon juice then causediscomfort, and dry air is poorly tolerated, whereas young skintolerates this without any problem.

These esthetic signs, such as wrinkles or fine lines, are such thatthere is a need in cosmetics for compounds which act on the skin toimprove the cellular vitality when it is detrimentally affected.

AMPK is present in all the cells of the body and plays the role ofenergy gauge therein. AMPK (or 5′-adenosine monophosphate activatedprotein kinase) is a heterotrimeric enzyme composed of a catalyticsubunit α with kinase activity and of two regulatory subunits β and γ.The activity of AMPK depends on the variation in the AMP/ATP ratio whichcharacterizes the energy level of the cell (ATP being hydrolyzed to giveAMP in order to “deliver” the energy required for the variousbiochemical processes of the cell). It is present in two forms,phosphorylated or non-phosphorylated, the phosphorylated form being theactive form.

When it is activated in response to an energy demand or to a stress ofthe cell, AMPK increases the energy-generating processes, such asglycolysis, and it inhibits the non-essential consuming processes, thusenabling cell survival. Preservation of the cellular energy status isinvolved in maintaining the longevity of the species and combating thesigns of aging. Thus, compounds which are capable of increasing theactivity of AMPK are at the present time the object of great interest inthe treatment of age-related clinical manifestations. The advantage intransposing this approach, validated for the whole body, to the skin inthe context of preventing age-related detrimental changes thereto isunderstood.

The AMPK activity corresponds to the cellular concentration ofphosphorylated AMPK. Thus, it is advisable to have the highest possiblelevels of phosphorylated protein in order to have this high activity.

The role of AMPK in controlling the energy metabolism of thekeratinocyte is suspected at the present time Prahl S et al.,Biofactors, 2008, 32(1-4), 245-55); its involvement in the proliferationand differentiation of the keratinocyte has been established (Saha A. K.et al., Biochem. Biophys. Res. Commun., 2006 Oct. 20, 349(2), 519-24).

WO 2004/05098 proposes to modulate the lifetime of any cell or of anorganism by controlling the activity of AMPK, and to treat age-relateddisorders by administering modulators of the AMPK metabolic pathway,without stating whether it involves an activator or an inhibitor.

Saha et al. (Biochem. Biophys. Res. Commun., 2006, 349:519-524) studiedthe AMPK-regulated growth of keratinocytes and conclude that AMPKactivators, such as AICAR, promote the in vitro differentiation ofkeratinocytes.

Moreover, it is also accepted that extrinsic factors, such asultraviolet rays, smoking or certain treatments (glucocorticoids,vitamin D and derivatives, for example), also have an effect on the skinand its collagen content.

Thus, prolonged exposure to ultraviolet radiation, particularly to typeA and B radiation, has the effect of stimulating the expression ofcollagenases, particularly of MMP1 (also known as matrixmetalloproteinase 1 or else interstitial collagenase), constituting oneof the components of photoinduced or non-photoinduced skin aging.

A certain number of active agents have already been proposed forpreventing and/or treating the signs of skin aging.

It is thus known to use specific hydroxylated compounds in order tostimulate collagen synthesis and/or the proliferation of fibroblasts ofthe dermis, as described in the French application FR 2 777 186.

Moreover, as previously mentioned, skin aging may be photoinduced, thatis to say that it may be caused following exposure to the sun. Thisextrinsic aging is then called photoaging or dermatoheliosis.

Conversely, “conventional” aging is sometimes called “chronologicalaging” or “intrinsic aging”.

Keratinous substances, and in particular the skin, are exposed daily tosunlight. In point of fact, it is known that prolonged exposure ofkeratinous substances, and in particular of the skin, to thispolychromatic light is capable of inducing skin disorders or elsesuperficial damage. This is in particular due to the formation of freeradicals, reactive oxygen entities such as O₂ ^(•−) and HO^(•), whichcan damage DNA, certain lipids and/or proteins, and more generally whichinduce cell aging. These reactive entities disrupt biological mechanismsby inducing oxidative stress. This contributes to the development andacceleration of cell degeneration.

The production of reactive oxygen entities therefore causes damage toDNA, to proteins and/or to lipids, and contributes to the accelerationof aging of the cells of the skin in particular.

Thus, the effects of oxidative stress affect cell respiration and resultin an accelerated aging of the skin, accompanied in particular by a dulland/or grey complexion, an uneven complexion, a loss of radiance and/ortransparency of the skin, the premature formation of wrinkles or finelines, and a loss of softness, suppleness and elasticity of the skin.

Thus, UV radiation induces a phenomenon termed “photoaging”, inparticular of the skin, which includes as associated signs theappearance of wrinkles/fine lines, a loss of radiance and an unevennessof the complexion, a loss of firmness, and the appearance of roughnessand of yellowing of the skin.

Exposure to the sun induces peroxidation of the surface lipids of theskin and in particular photoinduced peroxidation of lipids of sebaceousorigin, such as squalene. This is because it is known that lipids whichare at the surface of the skin are continuously subjected to externalattacks and in particular the air, atmospheric pollutants and visibleradiation and especially ultraviolet (UV) radiation, and that the mostexposed to external attacks are those present in the fatty secretions ofthe skin, such as sebum, which is rich in squalene. The presence in thesqualene molecules of six double bonds makes these molecules sensitiveto oxidation phenomena. Thus, during prolonged exposure to UV radiation,squalene becomes photoperoxidized to give squalene peroxides. This highproduction of squalene peroxides causes in particular a series of chaindegradations, in particular in and on the skin, giving rise to numerousskin disorders including photoaging.

Numerous agents or treatments for preventing and/or treating photoagingalready exist, such as vitamin A, botulinum toxin, skin filling agents,various laser treatments, dermabrasion and peels.

In addition, numerous antioxidants, used in the cosmetics industry forcombating free radicals, are already known.

The role of antioxidants is to capture and neutralize free radicals byconverting them into subentities, without danger to keratinoussubstances.

Antioxidants can therefore be used in various fields, such as antiagingcosmetics, and protection against oxidative stress and in particularthat caused by exposure to the sun.

Mention may in particular be made of vitamin E (α-tocopherols andisomers), vitamin C (ascorbic acid) and its derivatives, carotenoids,aminoindoles, melatonin, ubiquinone, coenzyme Q, green tea, thiols andtheir derivatives (glutathione, N-acetylcysteine), oligomericproanthocyanidins (OPCs), flavonoids, catechins, in particularepicatechin and also its gallic derivatives, polyphenols, such as, forexample, tyrosol, hydroxytyrosol, sesamol, carnosol, γ-orizanol, acidssuch as dihydrolipoic acid, uric acid, ferulic acid, caffeic acid,rosemarinic acid or carnosic acid, and also trans-resveratrol.

Resveratrol is furthermore an active agent of the family of thepolyphenols, the effectiveness of which is recognized in antiaging andas antioxidant but the formulation of which requires the use ofoptimized supports in order to ensure the solubility and thephotostability thereof.

However, there remains a constant need to have available new activeagents capable of exerting a beneficial cosmetic action with regard tothe signs of skin aging, in particular the chronological signs, or ofphotoaging, and also a protective action for keratinous substancesagainst the effects of UV radiation, in particular for combating freeradicals.

It is an object of the present invention to meet this need.

Unless otherwise specified, the term “signs of aging” encompassesintrinsic and extrinsic signs of aging, as defined below.

The term “mechanical properties” of the skin intends to mean theproperties of the skin in connection to its extensibility, tonicity,firmness, suppleness and/or elasticity.

In addition to the appearance of cutaneous signs of aging, it is alsopossible to observe, on the skin, the appearance of a nonuniformity ofthe complexion which may prove to be troublesome, or also some peoplemay be desirous of modifying their skin tone, for example of lighteningit and/or of whitening it.

In particular, at different periods of their lives, some people witnessthe appearance on the skin and more especially on the hands and the faceof darker and/or more highly colored blemishes which give the skin alack of uniformity. These blemishes are due in particular to a highconcentration of melanin in the keratinocytes situated at the surface ofthe skin.

An overall lightening action on the complexion or flesh tone of the skinmay also be desired, without necessarily corresponding to an appearanceof blemishes.

The use of inoffensive topical depigmenting substances which are highlyeffective is very particularly sought after with a view to treatingpigment blemishes.

The mechanism of formation of the pigmentation of the skin, that is tosay of the formation of melanin, is particularly complex and involves,schematically, the following main stages:

Tyrosine→Dopa→Dopaquinone→Dopachrome→Melanin

Tyrosinase (monophenol dihydroxyl phenylalanine: oxygen oxidoreductaseEC 1.14.18.1) is the essential enzyme involved in this sequence ofreactions. In particular, it catalyzes the conversion reaction oftyrosine to give dopa (dihydroxyphenylalanine), by virtue of itshydroxylase activity, and the conversion reaction of dopa to givedopaquinone, by virtue of its oxidase activity. This tyrosinase actsonly when it is in the maturation state under the effect of certainbiological factors.

A substance is recognized as depigmenting if it acts directly on thevitality of the epidermal melanocytes where melanogenesis takes placeand/or if it interferes with one of the stages of the biosynthesis ofmelanin, either by inhibiting one of the enzymes involved inmelanogenesis or by being inserted as structural analog of one of thechemical compounds in the sequence for the synthesis of melanin, whichsequence can then be blocked and thus ensure depigmentation.

Arbutin and kojic acid are known as depigmenting agents for the skin.

Substances have been sought which exhibit an effective depigmentingaction, in particular superior to that of arbutin and kojic acid.

The need remains for a novel whitening agent for human skin having anaction as effective as those known but not having their disadvantages,that is to say which are nonirritating, nontoxic and/or nonallergizingfor the skin and which can be easily formulated, while being stable in acomposition, or else alternatively which has a reinforced action so asto be able to be used in a lower amount, which considerably reduces theside effects liable to be observed.

In this regard, the applicant company has discovered, surprisingly andunexpectedly, that the compounds of formula (I) as defined below exhibita good depigmenting activity, even at low concentration, without showingcytotoxicity.

Thus, according to a first subject matter, the present invention relatesto the cosmetic use of at least one compound of formula (I):

in which:

denotes a divalent radical chosen from a carbon-carbon single bond*—CH₂—CH₂—* or double bond *—CH═CH—*, of Z or E configuration or theirmixtures,

b=0 or 1,

c=0 or 1,

d=0, 1 or 2,

it being understood that, if c=1, then d≥1 and the COOR′ group is in theortho position with respect to a phenol functional group, and

R and R′ independently denote a hydrogen atom, a linear C₁-C₆ alkylradical or a branched C₃-C₆ alkyl radical, preferably a hydrogen atom, alinear C₁-C₄ alkyl radical or a branched C₃-C₄ alkyl radical, one of itsstereoisomers and/or solvates and/or one of its salts, to treat and/orprevent signs of aging and/or of photoaging of keratinous substances,preferably of the skin, and/or to depigment, lighten and/or whitenkeratinous substances, preferably the skin.

According to a particular embodiment, the present invention is directedto a cosmetic use as defined above, wherein it is directed to combatand/or prevent the signs of aging of the keratinous substances and inparticular the skin, and in particular wherein it is directed to improvethe mechanical properties of the skin, for example firmness.

As set out below, the cosmetic use of compounds of formulae (II) and(II′) as are defined below also forms part of the invention, includingfor the same applications as described for the compounds of formula (I).

According to a second subject matter, the present invention relates to acompound of formula (III):

in which:

c=0 or 1,

it being understood that, if c=1, then the COOR′ group is in the orthoposition with respect to a phenol functional group, and

R and R′ independently denote a hydrogen atom, a linear C₁-C₆ alkylradical or a branched C₃-C₆ alkyl radical, preferably a hydrogen atom, alinear C₁-C₄ alkyl radical or a branched C₃-C₄ alkyl radical, one of itsstereoisomers and/or solvates and/or one of its salts.

As set out below, a compound of formula (III′) as defined below alsoforms part of the invention.

According to a third subject matter, the present invention relates to acompound of formula (IV):

in which:

c=0 or 1,

d=0, 1 or 2,

it being understood that, if c=1, then d≥1 and the COOR′ group is in theortho position with respect to a phenol functional group, and

R and R′ independently denote a hydrogen atom, a linear C₁-C₆ alkylradical or a branched C₃-C₆ alkyl radical, preferably a hydrogen atom, alinear C₁-C₄ alkyl radical or a branched C₃-C₄ alkyl radical, one of itsstereoisomers and/or solvates and/or one of its salts.

According to a fourth subject matter, the present invention also relatesto a compound of formula (V):

in which:

R denotes a linear C₁-C₆ alkyl radical or a branched C₃-C₆ alkylradical, preferably a linear C₁-C₄ alkyl radical or a branched C₃-C₄alkyl radical, one of its stereoisomers and/or solvates and/or one ofits salts.

Another subject matter of the present invention is a composition,preferably a cosmetic composition, comprising, in a physiologicallyacceptable medium, at least one compound of formula (III), (III′), (IV)or (V) as defined above.

The invention also relates to the cosmetic use of at least one of thecompounds of formula (III), (III′), (IV) or (V), of their stereoisomersand/or solvates and/or one of their salts.

Another subject matter of the present invention is a method for thecosmetic treatment of keratinous substances, in particular the skin,comprising the application, to the keratinous substances, of acomposition, preferably a cosmetic composition, comprising at least onecompound of formula (I), (II), (II′), (III), (III′), (IV) or (V), asdefined above and below.

The present invention also relates to a method for the nontherapeuticcosmetic treatment of keratinous substances as defined above, fortreating and/or preventing signs of skin aging and/or for protectingkeratinous substances, in particular the skin, from the effects of UVradiation.

Another subject matter of the invention is a method for thenontherapeutic cosmetic treatment of keratinous substances as definedabove, for depigmenting, lightening and/or whitening keratinoussubstances, in particular the skin.

Finally, the invention is targeted at a method for the cosmetictreatment of keratinous substances as claimed in the preceding claim,for treating and/or preventing signs of skin aging and/or for protectingkeratinous substances, in particular the skin, from the effects of UVradiation and/or for depigmenting, lightening and/or whiteningkeratinous substances, preferably the skin, in particular for combatingand/or preventing the signs of aging of keratinous substances,preferably the skin.

“Keratinous substances” is understood to mean, within the meaning of thepresent invention, the skin, whether the skin of the body, of the face,of the neck, of the hands or also of the armpits, the lips and the mucusmembranes.

“Cosmetic use” is understood to mean, within the meaning of theinvention, a nontherapeutic use.

As emerges from the following, the cosmetic use according to the firstaspect of the present invention is thus targeted at alleviating orpreventing the effects of aging of keratinous substances, and moreparticularly of the skin, whether it concerns:

intrinsic aging, being a matter for antiaging activity, which, as foundabove, results from a genetically programmed senescence where endogenousfactors are involved, or

extrinsic aging and in particular photoinduced aging, being a matter forphotoprotective activity, which is brought about subsequent to exposureto the sun.

Intrinsic Aging—Antiaging Activity

In the context of the present invention, the nontherapeutic cosmeticuse, for treating and/or preventing signs of intrinsic aging ofkeratinous substances, preferably skin aging, may be particularlyintended for the prevention and/or the treatment of intrinsic aging ofthe skin, such as the skin of the face, of the neck, of the body and ofthe hands and more preferably the skin of the face or of the neck.

Said intrinsic aging may in particular be related to glycation, tocutaneous homeostasis and/or to an increase in the AMPK activity.

One way of reversing the cutaneous homeostasis is to maintain the levelof hyaluronic acid sufficient in the extracellular matrix. This could bedone with a compound by the stimulation of the expression of the HAS3marker by keratinocytes, which is the gene coding for hyaluronic acidsynthase.

Thus, according to another embodiment, the invention concerns the use ofa compound of formula (I), (II), (II′), (III), (III′), (IV) or (IV′) asdefined above for the activation of the HAS3 marker by keratinocytes inskin.

According to a further embodiment, the invention is directed to thecosmetic use of a compound of formula (I), (II), (II′), (III) or (III′)as defined above for improving skin firmness.

It is also intended to target in particular any modification of theexternal appearance of the skin due to chronological aging, which ismanifested, for example, by wrinkles and fine lines, withered skin,flaccid skin, thinned skin, dull, lifeless skin, or lack of elasticityand/or of tone of the skin.

Thus, the present invention relates to the prevention and/or treatmentof wrinkles and/or fine lines and/or crevices, and of thinning of theskin.

According to the present invention, “treatment of wrinkles and/or finelines” is understood to mean the fact of softening wrinkles and/or finelines, or reducing the appearance of wrinkles and/or fine lines.

In addition, the compounds in accordance with the invention make itpossible to combat the loss of firmness and/or of elasticity and/or oftonicity and/or of suppleness and/or the slackening of the skin, andalso the radiance of the complexion.

Thus, the present invention relates to the improvement of the firmnessof the skin, in particular of mature and/or wrinkled skin, and/or theradiance of the complexion.

The present invention is also targeted at protecting a method for thenontherapeutic cosmetic treatment of the skin for treating and/orpreventing signs of skin aging, in particular chronological aging,comprising at least one stage consisting in applying, to the skin, acosmetic composition comprising at least one compound in accordance withthe present invention, in particular of formula (I), (II), (II′), (III),(III′), (IV) or (V).

Extrinsic Aging, in Particular Photoinduced Aging—PhotoprotectiveActivity

For the purposes of the present description, extrinsic aging is causedby physical or chemical attacks from the environment and mainly by UVradiation. Physical attacks from the environment include extremetemperatures.

Thus, in the context of the present invention, the present invention isalso targeted at protecting the nontherapeutic cosmetic use of acomposition containing, in a physiologically acceptable medium, at leastone compound of formula (I), (II), (II′), (III), (III′), (IV) or (V) forprotecting the skin from an oxidative stress caused by exposure of theskin to UV radiation, in particular for protecting the skin from anoxidative stress caused by repeated daily and/or prolonged exposure toUV radiation.

Depigmentation

The invention also relates to the nontherapeutic cosmetic use of atleast one compound of formula (I), (II), (II′), (III), (III′), (IV) or(V), as defined above and below, as whitening, lightening and/ordepigmenting agent for keratinous substances, in particular for theskin.

The compounds in accordance with the invention, namely the compounds offormulae (I), (II), (II′), (III), (III′), (IV) and (V) as defined below,make it possible to effectively depigment and/or lighten, indeed even towhiten, the skin of human beings. They can thus be intended to lightenoverall the complexion or flesh tone of the skin. They can also beintended to be applied to the skin of individuals exhibiting brownishpigmentation blemishes or blemishes due to aging, or to the skin ofindividuals desiring to combat the appearance of a brownish colororiginating from melanogenesis.

Compounds of Formula (I) Used According to the Invention

As already mentioned, the invention relates to the nontherapeuticcosmetic use, as agent for treating and/or preventing signs of skinaging, and/or as a photoprotective agent, in particular as anantioxidant, and/or for depigmenting, lightening and/or whiteningkeratinous substances, preferably the skin, of a composition containing,in a physiologically acceptable medium, at least one compound of formula(I) defined above and/or at least one of its solvates and/or of itsstereoisomers.

Within the meaning of the invention, a C₁-C_(x) alkyl radical is analkyl group comprising from 1 to x carbon atoms, in particular from 1 to6 carbon atoms or also from 1 to 4 carbon atoms, that is to say that thealkyl group may comprise, for example, 1, 2, 3, 4, 5 or 6 carbon atoms.Mention may be made, as examples of alkyl groups, of the methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl groups.

Preferably, the isomers according to the invention are stereoisomers, inparticular enantiomers, diastereoisomers, and also their mixtures,including racemic mixtures.

According to a preferred alternative form, the compounds of formula (I)are chosen from the diastereoisomers of E (trans) configuration.

The acceptable solvates of the compounds of formula (I) compriseconventional solvates. Mention may be made, by way of example, of thesolvates due to the presence of solvents. Mention may be made, by way ofexample, of the solvates due to the presence of water or of linear orbranched alcohols, such as ethanol or isopropanol.

The salts of the compounds of formulae (I), (II), (II′), (III), (III′),(IV) and (V) as defined below are organic and/or inorganic cations. Theycan be chosen from metal cations, for example aluminum (Al³⁺), zinc(Zn²⁺), manganese (Mn²⁺) or copper (Cu²⁺); alkali metal cations, forexample lithium (Li⁺), sodium (Na⁻) or potassium (K⁺); and alkalineearth metal cations, for example calcium (Ca²⁺) or magnesium (Mg²⁺).They can also be cations of formula NH₄ ⁻ or organic cations of formulaNHX₃ ⁺, NX₃ denoting an organic amine, the X radicals being identical ordifferent, it being possible for two or three X radicals to form, inpairs, a ring with the nitrogen atom which carries them or it beingpossible for NX₃ to denote an aromatic amine. The organic amines denotein particular alkylamines, such as, for example, methylamine,dimethylamine, trimethylamine, triethylamine or ethylamine;hydroxyalkylamines, such as, for example, 2-hydroxyethylamine,bis(2-hydroxyethyl)amine or tri(2-hydroxyethyl)amine; cycloalkylamines,such as, for example, bicyclohexylamine or glucamine, piperidine;pyridines and analogs, for example collidine, quinine or quinoline; andamino acids having a basic nature, such as, for example, lysine orarginine, the number and the nature of the cations depending on thevalency of these cations compared with the anionic part in order for thesalts of compounds of formula (I) to be neutral compounds overall. Inother words, when one at least of the radicals carried by one at leastof the aromatic rings of the compounds of formula (I), (II), (II′),(III), (III′), (IV) or (V) is anionic, the electrical neutrality of thecompounds of formula (I), (II), (II′), (III), (III′), (IV) or (V) isprovided by one or more identical or different cations defined above.

This definition of the salts is valid for all of the compounds inaccordance with the invention, whatever the compounds of formula (I),(II), (II′), (III), (III′), (IV) or (V).

According to a specific embodiment, the invention is targeted at thecompounds of formula (I) for which:

b=0 or 1, and

d=1 or 2,

and more particularly the compounds for which b+d≥2.

According to another specific embodiment, the invention is targeted atthe compounds of formula (I) for which b+d≥2 and R and R′ independentlyrepresent a hydrogen atom or an ethyl radical or one of their salts.

According to another specific embodiment of the invention, the inventionis targeted at the compounds of formula (I) for which R and R′ areidentical and denote a hydrogen atom or an ethyl radical or one of theirsalts and is preferably targeted at the compounds of formula (I) forwhich R and R′ denote a hydrogen atom or one of its salts.

According to an alternative form, the invention is targeted at thecosmetic use of at least one compound of formula (II):

in which:

denotes a divalent radical chosen from a carbon-carbon single bond*—CH₂—CH₂—* or double bond *—CH═CH—*, of Z or E configuration and theirmixtures,

c=0 or 1,

d′=1 or 2,

it being understood that, if c=1, then the COOR′ group is in the orthoposition with respect to a phenol functional group, and

R and R′ independently denote a hydrogen atom, a linear C₁-C₆ alkylradical or a branched C₃-C₆ alkyl radical, preferably a hydrogen atom, alinear C₁-C₄ alkyl radical or a branched C₃-C₄ alkyl radical, one of itsstereoisomers and/or solvates and/or one of its salts, to treat and/orprevent signs of aging and/or of photoaging of keratinous substances,preferably the skin, and/or to depigment, lighten and/or whitenkeratinous substances, preferably the skin.

Still in the context of this alternative form, and more preferablystill, the choice will be made of the compounds for which R and R′independently denote a hydrogen atom or an ethyl radical or one of theirsalts.

Among the compounds of formula (II), the choice will more preferably bemade of the compounds for which R and R′ are identical and represent ahydrogen atom or an ethyl radical or one of their salts. More preferablystill, the choice will be made of the compounds for which R and R′represent a hydrogen atom or one of its salts.

According to a specific embodiment of this alternative form, a subjectmatter of the invention is the cosmetic use of at least one compound offormula (II′):

in which:

denotes a divalent radical chosen from a carbon-carbon single bond*—CH₂—CH₂—* or double bond *—CH═CH—*, of Z or E configuration or theirmixtures,

c=0 or 1,

d″=0 or 1,

it being understood that, if c=1, then the COOR′ group is in the orthoposition with respect to a phenol functional group, and

R and R′ independently denote a hydrogen atom, a linear C₁-C₆ alkylradical or a branched C₃-C₆ alkyl radical, preferably a hydrogen atom, alinear C₁-C₄ alkyl radical or a branched C₃-C₄ alkyl radical, one of itsstereoisomers and/or solvates and/or one of its salts, to treat and/orprevent signs of aging and/or of photoaging of keratinous substances,preferably the skin, and/or to depigment, lighten and/or whitenkeratinous substances, preferably the skin.

Still in the context of this specific embodiment, and more preferablystill, the choice will be made of the compounds for which R and R′independently denote a hydrogen atom or an ethyl radical or one of theirsalts.

Among the compounds of formula (II′), the choice will more preferably bemade of the compounds for which R and R′ are identical and represent ahydrogen atom or an ethyl radical or one of their salts. More preferablystill, the choice will be made of the compounds for which R and R′represent a hydrogen atom or one of its salts.

Novel Compounds

As already indicated, the present invention also relates to the novelcompounds of formulae (III), (IV) and (V), as defined above.

Compounds of Formula (III)

The compounds of formula (III) can also be defined as compounds offormula (I) for which:

-   -   b=1 and the phenol functional groups are in the meta position        with respect to each other,    -   d=2, and    -   the divalent radical between the 2 aromatic rings is an        unsaturated radical —CH═CH—, of Z or E configuration or their        mixtures, preferably of E configuration.

According to a specific embodiment, the invention relates to thecompounds of formula (III) in which R and R′ independently denote ahydrogen atom, an ethyl radical or one of their salts.

According to an even more specific embodiment, the invention relates tothe compounds of formula (III) in which R and R′ are identical andrepresent a hydrogen atom or an ethyl radical or one of their salts.More preferably still, the choice will be made of the compounds forwhich R and R′ represent a hydrogen atom or one of its salts.

Mention may in particular be made, among the compounds of formula (III),of the compounds Y, Z, Y′, Y-Et, Z-Et and Y′-Et as defined below intable I, one of their stereoisomers and/or solvates and/or one of theirsalts.

Another subject matter of the invention is more particularly a compoundof formula (III) in which one of the phenol functional groups is in thepara position with respect to the divalent radical —CH═CH—, namely oneof formula (III′):

in which:

c=0 or 1,

it being understood that, if c=1, then the corresponding COOR′functional group is in the ortho position with respect to a phenolfunctional group, and

R and R′ independently denote a hydrogen atom, a linear C₁-C₆ alkylradical or a branched C₃-C₆ alkyl radical, preferably a hydrogen atom, alinear C₁-C₄ alkyl radical or a branched C₃-C₄ alkyl radical, one of itsstereoisomers and/or solvates and/or one of its salts.

More preferably still, the choice will be made of the compounds forwhich R and R′ independently denote a hydrogen atom or an ethyl radicalor one of their salts.

Among the compounds of formula (III′), the choice will more preferablystill be made of the compounds for which R and R′ are identical andrepresent a hydrogen atom or an ethyl radical or one of their salts.More preferably still, the choice will be made of the compounds offormula (III′) for which R and R′ represent a hydrogen atom or one ofits salts.

Mention may in particular be made, among the compounds of formula(III′), of the compounds Y, Z, Y′, Y-Et, Z-Et and Y′-Et and as definedbelow in table I, one of their stereoisomers and/or solvates and/or oneof their salts.

Compounds of Formula (IV)

The compounds of formula (IV) can also be defined as compounds offormula (I) for which:

-   -   b=1 and the two phenol functional groups are in the meta        position with respect to each other, and    -   the divalent radical between the 2 aromatic rings is a saturated        radical —CH₂—CH₂—.

According to a specific embodiment of the invention, it is targeted atthe compounds for which R and R′ independently denote a hydrogen atom oran ethyl radical or one of their salts.

Among the compounds of formula (IV), the choice will more preferably bemade of the compounds for which R and R′ are identical and represent ahydrogen atom or an ethyl radical or one of their salts. More preferablystill, the choice will be made of the compounds for which R and R′represent a hydrogen atom or one of its salts.

Mention may in particular be made, among the compounds of formula (IV),of the compounds X and X-Et as defined below in table I, one of theirstereoisomers and/or solvates and/or one of their salts.

Compounds of Formula (V)

The compounds of formula (V) can also be defined as compounds of formula(I) for which:

-   -   b=1 and the two phenol functional groups are in the meta        position with respect to each other,    -   c=0,    -   d=1 and the corresponding phenol functional group is in the para        position with respect to the divalent radical, said divalent        radical being an unsaturated radical —CH═CH—, and    -   R is a linear C₁-C₆ alkyl radical or a branched C₃-C₆ alkyl        radical, preferably a linear C₁-C₄ alkyl radical or a branched        C₃-C₄ alkyl radical.

According to a specific embodiment of the invention, R denotes an ethylradical.

Mention may in particular be made, among the compounds of formula (V),of the compound W-Et as defined below in table I, one of itsstereoisomers and/or solvates.

The compounds of formula (I) in accordance with the invention can becollated in the following table I:

TABLE I Compound Structure Substructure W

Non-novel compound (described in J. Mol. Catal. B: Enzymatic, 2015, 122,348) (I), (II), (II′) W-Et

Novel compound (I), (II), (II′), (V) X

Novel compound (I), (II), (II′), (IV) X-Et

Novel compound (I), (II), (II′), (IV) Y

Novel compound (I), (II), (III) and (III′) Y-Et

Novel compound (I), (II), (III) et (III′) Y′

Novel compound (I), (II), (III) et (III′) Y′-Et

Novel compound (I), (II), (III) et (III′) Z

Novel compound (I), (II), (III) et (III′) Z-Et

Novel compound (I), (II), (III) et (III′)

and also their salts and/or solvates and/or stereoisomers.

According to a specific embodiment of the invention, the invention ismore particularly targeted at the cosmetic use of the compound W asdescribed above, of one of its salts, solvates and/or isomers, moreparticularly still for the purpose of decreasing and/or delaying thesigns of aging of keratinous substances, and in particular of the skin,and/or also for the purpose of depigmenting and/or lightening and/orwhitening the skin.

The compounds in accordance with the present invention can be preparedaccording to the processes and schemes described below.

The compounds corresponding to the formula (I) can be prepared from thecorresponding polyphenols (A-I), for which b and d are as defined above,in one stage (carboxylation) if R=H or 2 stages (carboxylation and thenesterification) if R=alkyl, according to the following Scheme 1.

The carboxylation (monocarboxylation or multicarboxylation) reactioncan, for example, be a carboxylation biocatalyzed by an enzyme ofdecarboxylase type, such as:

-   -   the decarboxylase isolated from R. radiobacter,    -   the decarboxylase specific for 2,3-dihydroxybenzoic acid        isolated from Aspergillus oryzae,    -   the decarboxylase specific for 2,6-dihydroxybenzoic acid        isolated from Rhozobium sp., and    -   the decarboxylase specific for salicylic acid isolated from        Trichosporon moniliiforme.

The enzymes can be used in isolated form (as described, for example, inM. Sato et al., “Enzymatic carboxylation of hydroxystilbenes by theγ-resorcylic acid decarboxylase from Rhizobium radiobacter WU-0108 underreverse reaction conditions”, J. Mol. Catal. B: Enzymatic, 2015, 122,348) or else in the form of lyophilized whole cells, as described, forexample, in C. Wuensch et al., “Regioselective 1 ortho-carboxylation ofphenols catalyzed by benzoic acid decarboxylases: a biocatalyticequivalent to the Kolbe-Schmitt reaction”, RSC Adv., 2014, 4, 9673,according to Scheme 2 which follows.

The compound (A-I), in solution in water or in an organic solvent (suchas methanol, ethanol, tetrahydrofuran, acetonitrile, ethyl acetate,isopropanol, t-butanol, 1,6-dioxane, butan-1-ol, acetone, butanone,toluene, 2-methyltetrahydrofuran, n-heptane, cyclohexane, t-butyl methylether) or in a water/organic solvent mixture, can be added to a buffersolution at slightly acidic pH, for example a phosphate buffer at pH5-7, containing the enzyme or the whole cells (in a concentration of0.5-50 mg/ml). The concentration of the substrate can be adjusted tobetween 1 mM and 1M.

This mixture can subsequently be added to a 1-5M aqueous potassiumhydrogencarbonate KHCO₃ solution. The flask containing the reactionmedium can be sealed and stirred at 10-70° C. for 1 to 48 hours.

The reaction can be interrupted by addition of a strong acid, forexample HCl, until a pH of 0-3 is obtained. The aqueous phase thusobtained can be extracted several times using an organic solvent, suchas diethyl ether, ethyl acetate or dichloromethane. The organic phasescan be combined and dried over sodium sulfate. The solvents can beevaporated under reduced pressure and the residue can be purified bysilica gel column chromatography.

The esterification reaction can be carried out according to the methodsknown to a person skilled in the art for the esterification ofderivatives of salicylic acid type.

The intermediate to be esterified, in solution in the alcohol ROH, canbe heated at reflux in the presence of an inorganic acid, such as, forexample, HCl or H₂SO₄, for 1 to 24 hours. After returning to ambienttemperature, the reaction medium can be diluted by addition of water(1-10 volumes) and the product can be extracted several times using anorganic solvent, such as diethyl ether, ethyl acetate ordichloromethane. The organic phases can be combined and dried oversodium sulfate. The solvents can be evaporated under reduced pressureand the residue can be purified by silica gel column chromatography.

More particularly, the compounds of formulae (III) and (IV) can beprepared according to the method described below.

The compounds of formula (III), respectively (IV), can be prepared bycarboxylation of the precursors (A-III), for which d and c are asdefined above, respectively (A-IV), for which d and c are as definedabove, according to the same method as for the preparation of (I) from(A-I), according to the following Schemes 3 and 4:

During the preparation of a compound of formula (III), the first stageas reported above in Scheme 3 can give rise to the formation of acompound of following formula (VI):

Among these compounds of formula (VI), in which d and c are as definedabove, the following compounds, for which d=2 and c=0, are novel. Theirpreparation is illustrated in example 2 below.

With regard to them, the compounds of formula (V) can be prepared byesterification of the compound (W) according to the method described forthe preparation of (I), according to the following Scheme 5:

Cosmetic Composition

A composition suitable for the invention, namely intended for theimplementation of the invention, can be a cosmetic composition, and thuscomprises a physiologically acceptable medium.

“Physiologically acceptable medium” is understood to mean a mediumcompatible with keratinous substances, such as the skin, or any othercutaneous region of the body, of the face, of the armpits in particular,or also as are defined above. A physiologically acceptable medium ispreferably a cosmetically acceptable medium, that is to say a mediumdevoid of unpleasant odor, color or appearance, and which is completelycompatible with the topical administration route.

By way of example, a cosmetic composition used according to the presentinvention comprises an amount of between 0.001% and 30% by weight,preferably between 0.01% and 10% by weight, in particular between 0.5%and 5% by weight, with respect to the total weight of the composition,of at least one compound of formula (I), (II), (II′), (III), (III′),(IV) or (V), its salts, solvates and/or stereoisomers.

The composition in accordance with the invention is intended for atopical application.

The composition can additionally comprise any constituent normallyemployed in the envisaged application.

Mention may in particular be made of water, solvents, oils of mineral ororganic origin, waxes, pigments, fillers, surfactants, additionalcosmetic active agents other than the compounds of formula (I), (II),(II′), (III), (III′), (IV) or (V), or also polymers. For example, thecomposition according to the invention can comprise at least onecosmetic adjuvant chosen, for example, from water; organic solvents, inparticular C₂-C₆ alcohols and C₂-C₁₀ carboxylic acid esters, hydrocarbonoils, silicone oils, fluorinated oils, waxes, pigments, fillers, dyes,surfactants, emulsifiers, UV-screening agents, film-forming polymers,hydrophilic or lipophilic gelling agents, thickeners, preservatives,fragrances, bactericides and odor absorbers.

According to a specific form of the invention, the composition inaccordance with the invention can additionally also contain one or moredeodorant active agents and/or one or more antiperspirant active agents.

In the composition according to the invention, the compounds (I), (II),(II′), (III), (III′), (IV) and/or (V) can also be used together withadditional antiaging or photoprotective active agents other than thecompounds of formulae (I), (II), (II′), (III), (III′), (IV) and/or (V).

In the composition according to the invention, the compounds (I), (II),(II′), (III), (III′), (IV) and/or (V) can also be used together withadditional depigmenting active agents other than the compounds offormulae (I), (II), (II′), (III), (III′), (IV) and/or (V).

The composition according to the invention can also comprise at leastone additional cosmetic active agent other than the compounds offormulae (I), (II), (II′), (III), (III′), (IV) and/or (V), such as, forexample, desquamating agents, moisturizing agents, NO-synthaseinhibitors, dermo-decontracting agents, tightening agents, and theirmixtures.

Thus, the composition according to the invention can be provided in theform of an antiaging composition, in particular a care composition,intended to combat external signs of skin aging, and/or in the form of aphotoprotective composition and/or in the form of a depigmentingcomposition.

This composition can be provided in any formulation form normally usedin the cosmetics field; it can in particular be in the form of anoptionally gelled aqueous solution, of a dispersion of the optionallytwo-phase lotion type, of an emulsion obtained by dispersion of a fattyphase in an aqueous phase (O/W) or vice versa (W/O), or of a triple(W/O/W or O/W/O) emulsion or of a vesicular dispersion of ionic and/ornonionic type.

The composition of the invention can constitute, for example, a lotion,a gel, a cream or a milk, or also a stick, indeed even an aerosol.

Thus, the composition can comprise any constituent normally employed inthe topical application and administration envisaged.

Of course, a person skilled in the art will take care to choose this orthese optional additional compounds, and/or their amounts, such that theadvantageous properties of the compound of formula (I), (II), (II′),(III), (III′), (IV) or (V) used according to the invention are not, ornot substantially, detrimentally affected by the envisaged addition andsuch that the properties of the compositions resulting therefrom arecompatible with the topical route.

A composition according to the invention can have the form of a care ormakeup product for the face and/or body, and be packaged, for example,in the cream form in a jar or fluid form in a tube or in a pump-actionspray.

According to a preferred embodiment, a composition according to theinvention comprising at least one compound of formula (I), (II), (II′),(III), (III′), (IV) or (V) of the invention is formulated in anantiaging cream and/or in a cream for photoprotection and/or a cream fordepigmentation, indeed even a stick.

A composition according to the invention can be manufactured by anyknown process generally used in the cosmetics field.

Cosmetic Methods

The present invention also relates to a method for the nontherapeuticcosmetic treatment of keratinous substances, in particular of the skin,comprising the application, to said keratinous substances, of acomposition as defined according to the invention.

In some embodiments of this method, the composition is applied to matureand/or wrinkled skin.

In some embodiments of this method, the composition is applied to theskin of people who wish overall to lighten the complexion or flesh toneof their skin.

In some embodiments of this method, the composition is applied to skinexhibiting brownish pigmentation blemishes or blemishes due to aging orto the skin of individuals desiring to combat the appearance of abrownish color originating from melanogenesis.

The nontherapeutic cosmetic method of the invention is performed bytopically administering a composition in accordance with the invention.

The topical administration consists of the external application, to thekeratinous substances, in particular the skin, of cosmetic compositionsaccording to the usual technique for using these compositions.

By way of illustration, the cosmetic method according to the inventioncan be performed by application, for example daily, of a composition inaccordance with the invention, which can be formulated, for example, inthe form of a cream, gel, serum, lotion, emulsion, makeup-removing milkor aftersun composition.

According to another embodiment, the application is repeated, forexample from 1, 2 to 3 times daily for one day or more and generally foran extended period of at least 4 weeks, indeed even 4 to 15 weeks,indeed even more, with, if appropriate, one or more periods of stoppage.

According to a specific form of the invention, other agents intended tomake the appearance and/or the texture of the skin more attractive mayalso be added to the composition according to the invention.

The present invention also relates to the nontherapeutic use of acosmetic composition as defined above, for cosmetically preventingand/or treating signs of skin aging and/or for providing aphotoprotective effect, such as an antioxidant effect.

The present invention also relates to the nontherapeutic use of acosmetic composition as defined above, for cosmetically preventingand/or treating blemishes due to aging, for depigmenting the skin and/orfor whitening it and/or for lightening it.

The invention also relates to the nontherapeutic use of a composition asdefined in the present description, for improving the firmness of theskin.

Throughout the description, the expression “comprising a” should beunderstood as being synonymous with “comprising at least one”, unlessotherwise specified.

The expressions “between . . . and . . . ”, “of between . . . and . . .” and “ranging from . . . to . . . ” should be understood as meaninglimits included, unless otherwise specified.

The examples which follow are presented as nonlimiting illustrations ofthe invention.

EXAMPLES Example 1 Preparation of Compound X

The substrate (A-X), in solution in methanol (50 mg in 1 ml), is addedto 19 ml of a phosphate buffer solution at pH 5.5 containing the wholecells (651 mg, producing the decarboxylase specific for2,6-dihydroxybenzoic acid isolated from Rhozobium sp.). This mixture issubsequently added to a 3M aqueous potassium hydrogencarbonate KHCO₃solution. The flask containing the reaction medium is sealed and stirredat 30° C. for 24 hours.

The reaction is interrupted by addition of a 6M aqueous HCl solution,until a pH of 2 is obtained. The aqueous phase thus obtained isextracted 4 times with ethyl acetate (10 ml). The organic phases arecombined and dried over sodium sulfate. The solvent is evaporated underreduced pressure and the residue is purified by silica gel columnchromatography (dichloromethane/methanol: 90/10), to result in theproduct (X) in the form of an offwhite/yellow solid (yield: 45%).

The ¹H NMR spectrum and the mass spectrum are in accordance with theexpected structure.

Example 2 Preparation of the Compounds Y and Y′

Oxyresveratrol (A-Y), in solution in methanol (50 mg in 1 ml), is addedto 19 ml of a phosphate buffer solution at pH 5.5 containing the wholecells (651 mg, producing the decarboxylase specific for2,6-dihydroxybenzoic acid isolated from Rhozobium sp.). This mixture issubsequently added to a 3M aqueous potassium hydrogencarbonate KHCO₃solution. The flask containing the reaction medium is sealed and stirredat 30° C. for 24 hours.

The reaction is interrupted by addition of a 6M aqueous HCl solution,until a pH of 2 is obtained. The aqueous phase thus obtained isextracted 4 times with ethyl acetate (10 ml). The organic phases arecombined and dried over sodium sulfate. The solvent is evaporated underreduced pressure. The crude reaction product thus obtained correspondsto the mixture of (Y), (Y′) and (Y″):

The residue is purified by silica gel column chromatography(dichloromethane/methanol: 90/10), to isolate the product (Y) in theform of an offwhite/yellow solid (yield: 66%).

The ¹H NMR spectrum and the mass spectrum are in accordance with theexpected structure.

Example 3 Demonstration of the Depigmenting Activity

The effectiveness was demonstrated on the basis of the following test:

The evaluations of the effect of prevention of or of decrease in thepigmentation of the skin and/or of lightening of the latter can becarried out in the following way.

The measurement of the depigmenting activity (reduction in theproduction of melanin) of compounds of formula (I) was performed byassaying the melanin produced by normal human melanocytes in vitro asfollows.

First of all, normal human melanocytes are cultured and dispensed into384 wells. After 24 hours, the culture medium was replaced with a mediumcontaining compounds of formula (I) to be evaluated. The cells wereincubated for 72 hours before measurement of the final optical density,which measures the amount of melanin produced by the melanocytes. A doseeffect is performed using a wide concentration range of the compoundsevaluated. Thus, by making the concentrations and the measurements ofmelanin correspond, it is possible to determine an IC50 in μM:concentration at which 50% decrease in melanin synthesis is achieved.

The compound W was in particular tested and showed a depigmentingeffect.

Thus, the compound W shows an inhibiting effect on the production ofmelanin with an IC50 value of 25 μM, without cytotoxicity in theconcentration range tested. The measurements at the differentconcentrations are collated in table II below.

TABLE II Mean percentage Percentage Standard ConcentrationDepigmentation deviation 0.0002 125.6 4.6 0.0001 99.7 1.1 0.00005 76.72.9 0.000025 43.0 3.7 0.0000125 32.8 6.2 0.00000625 22.8 4.1 0.00000312515.6 2.0 1.5625*10⁻⁶ 9.7 1.7 7.8125*10⁻⁷ 5.5 4.3 3.90625*10⁻⁷  −0.9 2.9

Example 4 Demonstration of the Anti-Aging Activity

The effectiveness was demonstrated on the basis of the following tests:

The evaluations of the effect of activation of hyaluronic acid (HA)biosynthesis can be carried out in the following ways.

Gene Markers Expression

Human epidermal keratinocytes were seeded in 48 well-culture plate andcultured for 48 hours at 37° C. and 5% of CO₂ in culture medium withrenewal of culture medium after the first 24 hours. At the end ofincubation, culture medium was replaced by assay medium containing ornot (control) raw material and cells were incubated for additional 24hours. All experimental conditions were performed in n=3. At the end oftreatment, cells were washed twice in PBS (w/o CaCl₂, w/o MgCl₂) and RNAextraction was performed using MagMAX™-96 Total RNA Isolation Kit(Ambion cat no AM8130) according to manufacturer recommendation. RNAquantification and quality control were performed using Labchip GX(Perkin Elmer). Relative expression of selected markers was measured bytwo steps RT-qPCR. In a first step, a reverse transcription wasperformed using the Quantitect® Reverse transcription kit (QIAGEN) andaccording to manufacturer recommendation. Then, PCR experiments wereperformed using a LightCycler® 480 Real-Time PCR System measuring SYBR®Green incorporation (Roche).

The compound W was in particular tested and showed an effect on HAS3expression. Indeed, the compound W is able to increase the expression ofthe HAS3 marker without cytotoxicity at 30 μM, with a fold change of2.45 vs control. The measurements are collated in table III and figure Ibelow.

TABLE III Relative expression Fold change P Treatment Concentration (UA)(Nb) Mean sd (vs control) Control — 1.34E−03 0.9449488 1.00 0.06 —1.40E−03 0.99192853 1.50E−03 1.06312267 Compound W 30 μM 3.61E−032.55336543 2.45 0.10 4.11E−03 3.44E−03 2.43243293 3.32E−03 2.34957534

Thus, compound W is able to stimulate the expression of the HAS3 markerby keratinocytes, which is the gene coding for hyaluronic acid synthase.Hence, since hyaluronic acid is an important constituent ofextracellular matrix, playing major role for instance in mechanicalproperties of dermis, compound W has thus been proven as improving skinfirmness, and more largely as showing anti-aging effect.

Example 5 Example of Composition in Accordance With the Invention

The percentages of compounds shown are percentages by weight, withrespect to the total weight of the composition in which they arepresent.

Compound W  1% Carbomer (Carbopol 981 from Lubrizol) 1% AM Preservativesq.s. Water q.s. for 100% AM: Active material

The above composition, applied topically to the skin, makes it possibleto attenuate brown blemishes.

The invention claimed is:
 1. A method for the cosmetic treatment ofkeratinous substances, comprising applying to the keratinous substances,a composition, comprising at least one compound of formula (III):

wherein: c=0 or 1, wherein, if c=1, then the COOR′ group is in the orthoposition with respect to a phenol functional group, and R and R′independently denote a hydrogen atom, a linear C₁-C₆ alkyl radical or abranched C₃-C₆ alkyl radical, one of its stereoisomers and/or solvatesand/or one of its salts.
 2. A method for the cosmetic treatment ofkeratinous substances, comprising applying to the keratinous substances,a composition, comprising at least one compound of formula (III′):

wherein: c=0 or 1, wherein, if c=1, then the corresponding carboxylatefunctional group is in the ortho position with respect to a phenolfunctional group, and R and R′ independently denote a hydrogen atom, alinear C₁-C₆ alkyl radical or a branched C₃-C₆ alkyl radical one of itsstereoisomers and/or solvates and/or one of its salts.
 3. A method forthe cosmetic treatment of keratinous substances, comprising applying tothe keratinous substances, a composition, comprising, at least onecompound of formula (IV):

wherein: c=0 or 1, d=0, 1 or 2, wherein, if c=1, then d≥1 and the COOR′group is in the ortho position with respect to a phenol functionalgroup, and R and R′ independently denote a hydrogen atom, a linear C₁-C₆alkyl radical or a branched C₁-C₆ alkyl radical, one of itsstereoisomers and/or solvates and/or one of its salts.
 4. A method forthe cosmetic treatment of keratinous substances, comprising applying tothe keratinous substances, a composition, comprising at least onecompound of formula (V):

wherein: R denotes a linear C₁-C₆ alkyl radical or a branched C₃-C₆alkyl radical, one of its stereoisomers and/or solvates and/or one ofits salts.
 5. A method for the cosmetic treatment of keratinoussubstances comprising: applying to keratinous substances a compositioncomprising at least one compound of formula (W):

wherein the compound of formula (W) is used to depigment, lighten and/orwhiten keratinous substances.